The Role of Efferocytosis in Inflammatory Arthritis

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THE ROLE OF EFFEROCYTOSIS IN INFLAMMATORY ARTHRITIS Abstract Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints which affects 1 in 100 people globally and millions in the US alone. We noted marked presence of apoptotic cells in the inflamed joints of arthritic mice. Apoptosis is intricately linked with phagocytosis of apoptotic cells, also known as ‘efferocytosis’. The current dogma suggests that increased apoptotic cell persistence in tissues inevitably leads to pathology. However, our data presented in this application suggest that this dogma warrants further testing. First, we show that systemic injection of apoptotic cells effectively alleviates inflammation in arthritic mice. Further, cell-free apoptotic cell supernatants or even purified apoptotic cell-released metabolites potently suppress inflammatory arthritis. Finally, pharmacologic or genetic efferocytosis reduction (not complete ablation) also reduce inflammation in arthritic mice. Here, we will test the hypothesis that reduced efferocytosis alleviates inflammation in arthritis through increased release of anti-inflammatory mediators (from uncleared apoptotic cells) and enhanced corpse processing/degradation (due to reduced corpse load in phagocytes). We will pursue the following aims: 1. Using mice with pharmacologic or genetic decrease in efferocytosis, we will quantify multiple disease parameters in arthritis, determine the numbers of apoptotic cells in the inflamed joints, analyze the phagocyte response, and analyze the metabolomics of reduced cell clearance environments. 2. Generate and validate a new transgenic mouse model with tissue-specific, inducible reduction of efferocytosis. Our findings will further our understanding of efferocytosis in homeostasis and inflammation and could open new avenues in therapeutic designs for the treatment of rheumatoid arthritis.